title: Knockdown of AHR1A but not AHR1B exacerbates PAH and PCB-126 toxicity in zebrafish (Danio rerio) embryos.
abstract: Various environmental contaminants are known agonists for the aryl hydrocarbon receptor (AHR), which is highly conserved across vertebrate species. Due to gene duplication events before and after the divergence of ray- and lobe-finned fishes, many teleosts have multiple AHR isoforms. The zebrafish (Danio rerio) has three identified AHRs: AHR1A and AHR1B, the roles of which are not yet well elucidated, and AHR2, which has been shown to mediate the toxicity of various anthropogenic compounds including dioxins, polychlorinated biphenyls (PCBs), and polycyclic aromatic hydrocarbons (PAHs). In this study, we sought to explore the role of the two AHR1 isoforms in PAH- and PCB-induced toxicity in zebrafish embryos utilizing morpholino gene knockdown of the AHR isoforms. Knockdown of AHR1B did not affect the toxicity of PAH mixtures or PCB-126, whereas knockdown of AHR1A exacerbated the cardiac toxicity caused by PAH mixtures and PCB-126. Knockdown of AHR1A did not impact the mRNA expression of CYP1A, CYP1B1, and CYP1C1 in exposed embryos, but it did result in increased CYP1 activity in exposed embryos. As has been shown previously, knockdown of AHR2 resulted in protection from PAH- and PCB-induced cardiac deformities and prevented CYP1 enzyme activity in exposed embryos. Co-knockdown of AHR1A and AHR2 resulted in an intermediate response compared to knockdown of AHR1A and AHR2 individually; co-knockdown did not exacerbate nor protect from PAH-induced deformities and embryos exhibited an intermediate CYP1 enzyme activity response. In contrast, co-knockdown of AHR1A and AHR2 did protect from PCB-126-induced deformities. These results suggest that AHR1A is not a nonfunctional receptor as previously thought and may play a role in the normal physiology of zebrafish during development and/or the toxicity of environmental contaminants in early life stages.
authors.affiliation: Nicholas School of the Environment, Duke University, Box 90328, Durham, NC 27708, USA. Electronic address: lvtgarner@gmail.com.
authors.forename: Lindsey V T
authors.initials: LV
authors.lastname: Garner
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Brown
authors.forename: Richard T
authors.initials: RT
authors.lastname: Di Giulio
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D055785:Gene Knockdown Techniques; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism*; D014874:Water Pollutants, Chemical / Q000633:toxicity*; D015027:Zebrafish / Q000235:genetics / Q000502:physiology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C507975:Ahr1b protein, zebrafish; D011084:Polycyclic Aromatic Hydrocarbons; D020033:Protein Isoforms; D018336:Receptors, Aryl Hydrocarbon; D014874:Water Pollutants, Chemical; D029961:Zebrafish Proteins; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; C023035:3,4,5,3',4'-pentachlorobiphenyl
keywords: Aryl hydrocarbon receptor; Cardiotoxicity; Morpholino; PCB-126; Polycyclic aromatic hydrocarbon; Zebrafish